NMR has found increasing use since the early 1970's as a medical diagnostic tool, in particular as an imaging technique. The technique provides high resolution and differentiation of soft tissue without the use of potentially harmful radiation. For several years, radiologists believed that with the high contrast achieved in NMR imaging in soft tissues without the use of contrast agents, the use of contrast agents would not be necessary. However, it has recently been found that paramagnetic complexes can be used with advantage to achieve enhanced contrast in NMR imaging thereby extending the diagnostic utility of the technique.
The nuclei of many atoms have a property called spin which is associated with a small magnetic moment. In the absence of an external magnetic field, the distribution of the orientations of the magnetic moments is random. In the presence of a static magnetic filed the nuclear magnetic moments process about the field direction and there will be a net alignment in the field.
In NMR imaging, a patient is placed in a static field and a short radio frequency pulse is applied via a coil surrounding the patient. The radio frequency or RF signal is selected for the specific nuclei which are to be resonated. The RF pulse causes the magnetic moments of the nuclei to align with the new field and to process in phase, and on termination of the pulse moments return to the original distribution of alignments with respect to the static field and to a random distribution of procession phases giving off a nuclear magnetic resonance signal which can be picked up by a receiving coil. The NMR signal is generally from .sup.1 H nuclei and represents a proton density of the tissue being studied. R. S. First, NMR In Medicine In The 1980's (1983).
Two additional values can be determined when the RF pulse is turned off and the nuclear magnetic moments are relaxing or returning to equilibrium orientations and phases. These are T1 and T2, the spin-lattice and spin-spin relaxation times. T1 represents a time characteristic of the return to equilibrium spin distribution, i.e. equilibrium alignment of the nuclear magnetic moments in the static field. T2 on the other hand represents a time characteristic of the return to random precession phase distribution of the nuclear magnetic moments.
The NMR signal that is generated thus contains information on proton density, T1 and T2 and the images that are generated are generally the result of complex computer data reconstruction on the basis of that information.
The potential application of contrast agents in extending the diagnostic utility of NMR imaging is discussed, for example, by R. C. Brasch in Radiology 147:781 (1983). Although numerous methods of contrast are available, many, such as manipulation of tissue temperature, viscosity or hydration, are clearly not clinically feasible and the most advantageous prior art technique appears to be the use of paramagnetic contrast agents to reduce the spin-lattice relaxation of time T1.
A paramagnetic substance is one which contains one or more fundamental particles (electrons, protons or neutrons) with a spin whose effect is not cancelled out by another particle with like spin. These particles create a small magnetic field which can interact with neighboring nuclear magnetic dipoles to cause a reorientation of the dipole, i.e. a change in nuclear spin and precession phase.
Since the magnetic field created by an electron is much greater than that created by a proton or a neutron, in practice only ions, molecules, radicals or complexes, which are paramagnetic due to the presence of one or more unpaired electrons, are used as paramagnetic NMR contrast agents.
The contrast effect of paramagnetic ions and complexes is predominantly the result of reduction in T1. However, paramagnetic stable free radicals will also cause some reduction in T2. R. C. Brasch, Radiology, 147:781 (1983). Nevertheless the relative reduction of T1 is greater than that of T2.
The use of paramagnetic contrast agents in NMR imaging has been extensively investigated and solutions and colloidal dispersions of such agents have been proposed for oral and paraenteral administration in conjunction with diagnostic imaging.
Ferromagnetic materials have also been used as contrast agents because of their ability to decrease T2. Medonca-Dias and Lauterbur, Magn. Res. Med., 3:328 (1986); Olsson et al, Mag. Res. Imaging, 4:437 (1986). Ferromagnetic materials have high, positive magnetic susceptibilities and maintain their magnetism in the absence of an applied field. The use of ferromagnetic materials as MRI contrast agents are described, for example, in PCT Application No. WO86/01112 and PCT Application No. WO85/043301.
A third class of magnetic materials, termed superparamagnetic materials, have been used as contrast agents. Saini et al., Radiology, 167:211 (1987); Hahn et al., Soc. Mag Res. Med. 4(22):1537 (1986). Like paramagnetic materials, superparamagnetic materials are characterized by an inability to remain magnetic in the absence of an applied magnetic field. Superparamagnetic materials can have magnetic susceptibilities nearly as high as ferromagnetic materials and far higher than paramagnetic materials. Bean and Livingston, J. Appl. Phys., Supp. 1 to Vol. 30, 1205, (1959).
Ferromagnetism and superparamagnetism are properties of lattices rather than ions or gases. Iron oxides such as magnetite and gamma ferric oxide exhibit ferromagnetism or superparamagnetism depending on the size of the crystals comprising the material, with larger crystals being ferromagnetic. G. Bate In: Ferromagnetic Materials, Vol. 2, Wohlfarth (ed.) p. 439.
As generally used, superparamagnetic and ferromagnetic materials alter the MR image by decreasing T2 resulting in image darkening. When injected, crystals of these magnetic materials accumulate in the targeted organs or tissues and darken the organs or tissues where they have accumulated.
Superparamagnetic particles have also been shown to be effective for the delivery and targeting of drugs directly to an infected organ, tissue or joint. Delivery systems, for example, using magnetic particles 100 Angstroms (A) in diameter encapsulated in albumin microspheres have been demonstrated for delivery of chemotherapeutic agents into Yoshida rat sarcoma. Widder, U.S. Pat. No. 4,345,588 (1982); Senyei et al., U.S. Pat. No. 4,357,259 (1982).
All of the aforementioned in vivo applications have the marked disadvantage of the lack of particle or cluster biodegradability. Half lives of Fe.sub.3 O.sub.4 100 A particles, for example, are in excess of 8 months when injected into a patient's body.
Particles of less than 50 A in diameter will generally clear from a patient after in vivo application very quickly; however, below 50 A in diameter there is no evidence of domain wall support and particles of this size are non-magnetic.